A potential role of Ras-mediated signal transduction for the enhancement of depolarization-induced Ca2+ responses in hippocampal neurons by basic fibroblast growth factor

Brain Res Dev Brain Res. 1998 Dec 7;111(2):169-76. doi: 10.1016/s0165-3806(98)00134-5.

Abstract

Chronic treatment with basic fibroblast growth factor (bFGF) increases the expression of functional L-type voltage-dependent Ca2+ channels (VDCCs) in fetal rat hippocampal neurons. We investigated the intracellular signaling mechanisms involved in this effect, using high K+ depolarization-induced elevation of intracellular Ca2+ concentrations as a measure. Genistein, a protein tyrosine kinase inhibitor, significantly attenuated the effect of bFGF. The effect of bFGF was also diminished by concurrent application of a Ras inactivator, N-acetyl-S-farnesyl-l-cysteine. In contrast, a phospholipase C inhibitor U73122, a phosphatidylinositol-3 kinase inhibitor wortmannin, Li+ which inhibits inositol phospholipid turnover, or a protein kinase inhibitor calphostin C did not inhibit the effect of bFGF. Phorbol 12-myristate 13-acetate, a protein kinase C activator, did not mimic the effect of bFGF. On the other hand, an adenylyl cyclase activator forskolin and a cyclic AMP analog 8-Br-cyclic AMP markedly attenuated the effect of bFGF, which indicates the presence of a cyclic AMP-mediated negative regulatory mechanism, possibly the interference of Ras-Raf interaction. These results suggest that Ras-mediated signal transduction is required for the enhancement by bFGF of VDCC responses in hippocampal neurons.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Androstadienes / pharmacology
  • Animals
  • Antimanic Agents / pharmacology
  • Calcium / metabolism*
  • Calcium Channels / physiology
  • Calcium Channels, N-Type*
  • Carcinogens / pharmacology
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Estrenes / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology*
  • Hippocampus / cytology
  • Lithium Chloride / pharmacology
  • Membrane Potentials / drug effects
  • Naphthalenes / pharmacology
  • Neurons / chemistry*
  • Neurons / cytology
  • Neurons / enzymology
  • Phosphodiesterase Inhibitors / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Pyrrolidinones / pharmacology
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Wortmannin
  • ras Proteins / metabolism*

Substances

  • Androstadienes
  • Antimanic Agents
  • Calcium Channels
  • Calcium Channels, N-Type
  • Carcinogens
  • Enzyme Inhibitors
  • Estrenes
  • Naphthalenes
  • Phosphodiesterase Inhibitors
  • Pyrrolidinones
  • voltage-dependent calcium channel (P-Q type)
  • Fibroblast Growth Factor 2
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Cyclic AMP
  • Proto-Oncogene Proteins c-raf
  • Protein Kinase C
  • ras Proteins
  • Lithium Chloride
  • calphostin C
  • Tetradecanoylphorbol Acetate
  • Calcium
  • Wortmannin